Posttranscriptional Regulation of Intestinal Mucosal Growth and Adaptation by Noncoding RNAs in Critical Surgical Disorders

Figures & data

Figure 1. miRNAs regulate the intestinal epithelium homeostasis by altering IEC survival, proliferation, migration, and cell-to-cell interaction. In this model, the levels of mucosal miRNAs are increased in the intestine after exposure to various pathological stresses. Increased miRNAs inhibit expression of their target genes by decreasing stability and translation of the mRNAs, thus leading to disruption of the gut epithelium homeostasis. RNA binding proteins (RBPs) such as HuR and CUGBP1 can interact with miRNAs including miR-195 and miR-222 and modulate their regulatory functions antagonistically or synergistically.

Table 1. Functions and targets of miRNAs in the intestinal epithelium.

Names	Major functions and targets	References
miR-222	Inhibits mucosal growth, delays wound healing Disrupts intestinal barrier function Downregulates Wnt signal and CDK4 Levels increase considerably in pathologic stress	[33–35]
miR-29b	Inhibits mucosal generation and gut barrier function Targets CDK2, claudin-1, and Menin	[40–42] [43,44]
miR-195	Impairs mucosal regeneration and adaptation Inhibits rapid restitution and wound healing Targets STMI1 and IGFR Interacts with uc.173	[45,50,51] [45,49]
miR-125a/214	Increases apoptosis Levels increase after massive intestine resection	[50] [52,53]
miR-503/322	Protects against apoptosis and increases proliferation Decreases in the state of mucosal atrophy	[56,58]
miR-16	Elicits G1 phase growth arrest in IEC	[21]
miR-146a	Regulates immune tolerance Represses Toll-like receptor Regulates protection against bacteria	[58]
miR-let-7e-5p	Impairs barrier integrity Inhibits expression of claudin-1 and E-cadherin	[60]
miR-429	Disrupts barrier function by targeting occludin	[61]
miR-21	Its levels increase by Type 1 diabetes Regulates inflammation and injury Increases in IBD and bowel obstruction	[62]
miR-29a	Regulates intestinal permeability in irritable bowel syndrome	[63]
miR-125b	Regulates tight junction proteins Interacts with miR-16	[64]
miR-200c	Increases gut permeability by targeting occludin	[65]
miR-144	Regulates gut permeability via occludin and ZO1	[66]

Figure 2. LncRNA H19 disrupts the intestinal defense and barrier function via distinct mechamisms. Induced levels of mucosal H19 in the intestine by septic stress and mucosal inflammation repress expression of tight junctions (TJs) and adherens junctions (AJs), impair autophagy, and disrupt function of Paneth cells (PCs) and goblet cells. H19 inhibits expression of ZO-1 and E-cadherin posttranscriptionally through release of miR-675 embedded in H19 exon 1, and this inhibition is prevented by HuR.

Table 2. Function of lncRNA in the intestinal epithelium.

Names	Functions and targets	References
uc.173	Stimulates mucosal growth by decreasing miR-195 Protects gut barrier by interacting with miR-29b	[72] [42]
uc.230	Regulates regeneration, apoptosis, and barrier integrity Interacts with CUGBP1	[73]
SPRY4-IT1	Protects gut barrier by enhancing tight junctions Interacts with HuR	[77]
H19	Disrupts gut barrier by reducing junction proteins Impairs function of Paneth and goblet cells	[81] [80]
Gata6	Regulates ISC proliferation via WNT signals	[84]
BMP1	Promotes mucosal healing via miR-128	[4]
PlncRNA1	Protects epithelial barrier by interacting with miR-34c	[86]
CCAT1	Increases inflammation by sponging miR-185-3p	[87]
BC012900	Inhibits cell proliferation and increases apoptosis	[88]
NAIL	Plays a role in colitis via NFκB activity Inactivates Wip1 by interacting with miR-148-3p	[89]

Figure 3. Model proposed to explain the influence of circHIPK3 upon intestinal epithelial repair after wounding. The levels of circHIPK3 are markedly altered in the intestinal mucosal tissues from patients with sepsis, Crohn’s disease, and ulcerative colitis. Increased circHIPK3 plays an essential role in intestinal mucosal repair after injury via interaction with miR-29b.

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